Congenital Dislocation of the Hip

Based on a Dissertation read before the Society on January 19th. 1962.The subject of Congenital Dislocation of the hip (C.D.H.) is so vast and complicated that anyone who attempts to correlate the known facts and numerous hypotheses into a neat, compact monograph, is doomed to failure before he starts. One of the main difficulties is the almost universal disagreement about the various aspects of the disease, whether of aetiology, pathology, diagnosis or treatment. In these pages, I shall confine myself to discussing some of the active steps one can take in the prevention and cure of the condition

Resilience: Easy to use but hard to define

First conceptualized in the 1970s, resilience has become a popular term in the ecological literature, used in the title, abstract, or keywords of approximately 1% of papers identified by ISI Web of Science in the field of environmental sciences and ecology in 2011. However, many papers make only passing reference to the term and do not explain what resilience means in the context of their study system, despite there being a number of possible definitions. In an attempt to determine how resilience is being used in ecological studies, we surveyed 234 papers published between 2004 and 2011 that were identified under the topic “resilience” by ISI Web of Science. Of these, 38% used the word resilience fewer than three times (often in the abstract or keyword list), 66% did not define the term, and 71% did not provide a citation to the resilience literature. Studies that defined resilience most often discussed it as pertaining to an entire ecosystem under continuous rather than discrete disturbance. Given the complex nature of this concept, we believe that care should be taken to properly describe what is meant by the term resilience in ecological studies

Reply to Crawford et al.: Why Trap-Neuter-Return (TNR) Is an Ethical Solution for Stray Cat Management

The recently published article, ‘A Case of Letting the Cat out of the Bag—Why Trap-Neuter-Return Is Not an Ethical Solution for Stray Cat (Felis catus) Management,’ by Crawford et al. warrants rebuttal. The case presented in the paper, opposing the initiation of TNR trials in Australia, ignores peer-reviewed evidence which substantiates the effectiveness of TNR at reducing unowned urban cat numbers. In addition, the paper’s authors offer a number of unrealistic recommendations, which are little more than a rebranding of the failed status quo. Urban stray cats have long been considered a problem across Australia. Current practice calls for the trapping and killing of thousands of healthy urban stray cats and kittens each year with no apparent effect on the total population. In contrast, the literature offers numerous examples, including two recent studies in Australia, of reductions in urban stray cat numbers where TNR has been implemented. TNR has also been associated with reduced feline intake and euthanasia at shelters, which improves both animal welfare and the well-being of shelter staff. A large-scale trial of TNR in an urban Australian context is scientifically justified and long overdue

Structure of S. aureus HPPK and discovery of a new inhibitor

The first structural and biophysical data on the folate pathway enzyme and drug target, 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), from the pathogenic bacterium Staphylococcus aureus is presented. HPPK is the second essential enzyme in the folate biosynthesis pathway, responsible for catalysing pyrophosphoryl transfer from cofactor (ATP) to the substrate (6-hydroxymethyl- 7,8-dihydropterin, HMDP). In-silico screening led to the discovery of a substrate competitive inhibitor, San1, which was subsequently co-crystallised with HPPK. A 1.65 Å resolution x-ray structure showed this to bind at the pterin site sharing many of the key intermolecular interactions of the substrate. ITC and SPR measurements yielded an equilibrium binding constant, Kd, of ~13 μM for San1. An IC50 of ~12 μM was determined by means of a new convenient tri-enzyme-coupled spectrophotometric assay. ITC and SPR further showed that the San1 inhibitor has no requirement for magnesium or ATP cofactor for competitive binding to the substrate site. According to 15N heteronuclear NMR measurements, the fast motion of the pterin loop (L2) is partially dampened in the ternary complex between SaHPPK, HMDP and , -methylene adenosine 5-triphosphate (AMPCPP), but the ATP loop (L3) remains mobile on the μs timescale. In contrast, for the SaHPPK/San1/AMPCPP ternary complex, loop L2 becomes rigid on the fast timescale and loop L3 becomes more ordered which are supported by a large entropic penalty associated with San1 binding as revealed by ITC. Backbone assignments and chemical shift perturbations implicate the sulphur in San1 as a likely important loop L2/L3 stabilizing mediato

Integral membrane protein structure determination using pseudocontact shifts.

Obtaining enough experimental restraints can be a limiting factor in the NMR structure determination of larger proteins. This is particularly the case for large assemblies such as membrane proteins that have been solubilized in a membrane-mimicking environment. Whilst in such cases extensive deuteration strategies are regularly utilised with the aim to improve the spectral quality, these schemes often limit the number of NOEs obtainable, making complementary strategies highly beneficial for successful structure elucidation. Recently, lanthanide-induced pseudocontact shifts (PCSs) have been established as a structural tool for globular proteins. Here, we demonstrate that a PCS-based approach can be successfully applied for the structure determination of integral membrane proteins. Using the 7TM α-helical microbial receptor pSRII, we show that PCS-derived restraints from lanthanide binding tags attached to four different positions of the protein facilitate the backbone structure determination when combined with a limited set of NOEs. In contrast, the same set of NOEs fails to determine the correct 3D fold. The latter situation is frequently encountered in polytopical α-helical membrane proteins and a PCS approach is thus suitable even for this particularly challenging class of membrane proteins. The ease of measuring PCSs makes this an attractive route for structure determination of large membrane proteins in general.This work was supported by the Biotechnology and Biological Sciences Research Council BBSRC [BB/K01983X/1].This paper was originally published in the Journal of Bimolecular NMR (Crick DJ, Wang JX, Graham B, Swarbrick JD, Mott HR, Nietlispach D, Journal of Biomolecular NMR 2015, doi:10.1007/s10858-015-9899-6)

Re-thinking and re-positioning ‘being in the moment’ within a continuum of moments : introducing a new conceptual framework for dementia studies

This article draws upon six social research studies completed by members of the Dementia and Ageing Research Team at The University of Manchester and their associated networks over an eight-year period [2011-2019] with the aim of constructing a definition of ‘being in the moment’ and situating it within a continuum of moments that could be used to contextualise and frame the lived experience of dementia. Using the approach formulated by Pound et al.(2005) to synthesising qualitative studies, we identified this continuum of moments as comprising four sequential and inter-linked steps: i) ‘Creating the moment’, defined as the processes and procedures necessary to enable being in the moment to take place. The time necessary for this to occur can range from fleeting to prolonged; ii) ‘Being in the moment’, which refers to the multi-sensory processes involved in a personal or relational interaction and embodied engagement. Being in the moment can be sustained through creativity and flow; iii) ‘Ending the moment’, defined as when a specific moment is disengaged. This can be triggered by the person(s) involved consciously or subconsciously, or caused by a distraction in the environment or suchlike; and iv) ‘Reliving the moment’, which refers to the opportunity for the experience(s) involved in ‘being in the moment’ to be later remembered and shared, however fragmentary, supported or full the recall

An ultracold molecular beam for testing fundamental physics

We use two-dimensional transverse laser cooling to produce an ultracold beam of YbF molecules. Through experiments and numerical simulations, we study how the cooling is influenced by the polarization configuration, laser intensity, laser detuning and applied magnetic field. The ultracold part of the beam contains more than $2 \times 10^5$ molecules per shot and has a temperature below 200 $\mu$K, and the cooling yields a 300-fold increase in the brightness of the beam. The method can improve the precision of experiments that use molecules to test fundamental physics. In particular, the beam is suitable for measuring the electron electric dipole moment with a statistical precision better than $10^{-30}$ e cm.Comment: 25 pages, 14 figures. Trajectory simulations added and results compared to experiment; other minor revision

Does stress perfusion imaging improve the diagnostic accuracy of late gadolinium enhanced cardiac magnetic resonance for establishing the etiology of heart failure?

Background Late gadolinium enhanced cardiovascular magnetic resonance (LGE-CMR) has excellent specificity, sensitivity and diagnostic accuracy for differentiating between ischemic cardiomyopathy (ICM) and non-ischemic dilated cardiomyopathy (NICM). CMR first-pass myocardial perfusion imaging (perfusion-CMR) may also play role in distinguishing heart failure of ischemic and non-ischemic origins, although the utility of additional of stress perfusion imaging in such patients is unclear. The aim of this retrospective study was to assess whether the addition of adenosine stress perfusion imaging to LGE-CMR is of incremental value for differentiating ICM and NICM in patients with severe left ventricular systolic dysfunction (LVSD) of uncertain etiology. Methods We retrospectively identified 100 consecutive adult patients (median age 69 years (IQR 59–73)) with severe LVSD (mean LV EF 26.6 ± 7.0%) referred for perfusion-CMR to establish the underlying etiology of heart failure. The cause of heart failure was first determined on examination of CMR cine and LGE images in isolation. Subsequent examination of complete adenosine stress perfusion-CMR studies (cine, LGE and perfusion images) was performed to identify whether this altered the initial diagnosis. Results On LGE-CMR, 38 patients were diagnosed with ICM, 46 with NICM and 16 with dual pathology. With perfusion-CMR, there were 39 ICM, 44 NICM and 17 dual pathology diagnoses. There was excellent agreement in diagnoses between LGE-CMR and perfusion-CMR (κ 0.968, p<0.001). The addition of adenosine stress perfusion images to LGE-CMR altered the diagnosis in only two of the 100 patients. Conclusion The addition of adenosine stress perfusion-CMR to cine and LGE-CMR provides minimal incremental diagnostic yield for determining the etiology of heart failure in patients with severe LVSD

Redefining the Expression and Function of the Inhibitor of Differentiation 1 in Mammary Gland Development

The accumulation of poorly differentiated cells is a hallmark of breast neoplasia and progression. Thus an understanding of the factors controlling mammary differentiation is critical to a proper understanding of breast tumourigenesis. The Inhibitor of Differentiation 1 (Id1) protein has well documented roles in the control of mammary epithelial differentiation and proliferation in vitro and breast cancer progression in vivo. However, it has not been determined whether Id1 expression is sufficient for the inhibition of mammary epithelial differentiation or the promotion of neoplastic transformation in vivo. We now show that Id1 is not commonly expressed by the luminal mammary epithelia, as previously reported. Generation and analysis of a transgenic mouse model of Id1 overexpression in the mammary gland reveals that Id1 is insufficient for neoplastic progression in virgin animals or to prevent terminal differentiation of the luminal epithelia during pregnancy and lactation. Together, these data demonstrate that there is no luminal cell-autonomous role for Id1 in mammary epithelial cell fate determination, ductal morphogenesis and terminal differentiation